In the initial funding period of this grant we first proposed the concept of a potentially safer vaccine approach for AD using A[unreadable] homologous peptides which are non-toxic and non-fibrillogenic. In addition we pioneered the use of gadolinium labeled A[unreadable]3 ligands for in vivo detection of amyloid lesions in Tg AD mice. In this revised competing continuation we focus on our immunological approaches to bring them closer to potential clinical use. Extensive data from many groups has shown that in AD model animals vaccination against A(3 is an effective means of preventing amyloid deposition, in association with cognitive benefits. More limited data from the aborted human active vaccination trial suggests that this approach can lead to amyloid clearance and cognitive improvement. However encephalitis occurred in 6% of patients, which has been linked to excessive cell mediated immunity. In our further studies we plan to avoid this toxicity by using our non-toxic A[unreadable] homologous peptides which have the T-cell epitopes removed or altered in conjunction with adjuvants that primarily stimulate a humoral immune response and are appropriate for human use. These include alum and Salmonella vaccine strains. A further potential toxicity linked with vaccination is hemorrhage associated with cerebral amyloid angiopathy (CAA), which we will address in our planned studies. This is an important issue as almost all AD patients at autopsy have CAA, with about 20% having severe CAA. The specific aims are: 1) Assess vaccination with two of our A[unreadable] homologous immunogens using alum as an adjuvant in AD Tg models that either have predominantly parenchymal amyloid versus vascular amyloid deposition. Vaccination will be initiated at the start of deposition and also after deposition is established. 2) Assess mucosal vaccination using attenuated Salmonella expressing our A[unreadable] homologous immunogens via an oral route. 3) Vaccinated animals will be characterized behaviorally. The amyloid burden will be determined as well as levels of soluble/insoluble/oligomeric A[unreadable]. In a subset of animals, whether clearance of existing amyloid deposits occurs will be determined in vivo using 2-photon microscopy. The Th-1 versus Th-2 response will be monitored by assessing cytokine production and specific antibody titers. Lay Summary: Active vaccination is an potential exciting therapy for AD;however, it can only be applied to patients if effective methods which are non-toxic can be developed. This application seeks to verify if this is possible.